CD4+ T cells control the immune response to viral infections and to nascent cancers. They provide specific directions to immunologic effector cells including macrophages, B cells, natural killers, and CD8+ T cells, and endow the adaptive immune system with the capacity to remember past encounters and to respond in a rapid, coordinated, and sustained fashion. The cardinal event in the escape of tumors from immune surveillance is the functional decapitation of tumor-specific CD4+ T cells, resulting in the paralysis, or ?exhaustion?, of anti- tumor effector cells. In the absence of CD4+ T cell help, tumor-specific CD8+ T cells upregulate expression of an inhibitory receptor, PD-1, and become unable to secrete cytokines or to kill tumor targets. Monoclonal antibodies that block PD-1 ?release the brakes? on anti-tumor T cells. However, PD-1 blockade attacks a symptom and not the cause of the escape from immune surveillance: the loss of CD4+ T cell help. There are no known methods for reversing tolerance in a patient?s tumor specific CD4+ T cells. Fortunately, CD4+ T cells from healthy donors can provide the same instructions to revive the endogenous anti-tumor immune response. The effectiveness of this approach was shown in a recent trial in which standard chemotherapy plus 3 doses of mismatched related donor lymphocyte infusions (DLI) produced a complete remission (CR) in 80% and two- year disease-free survival of 39% compared to current therapy of 43% CR and 10% two-year disease-free survival. However, the presence of CD8+ T cells in the DLI can be associated with unacceptable toxicities such as sustained donor cell engraftment and lethal graft-versus-host disease (GVHD)., and the use of related donors may foreclose the possibility of subsequent allogeneic stem cell transplantation from a family donor. The Johns Hopkins University is collaborating with the sponsor of IND 17305 (Cellunova LLC) to develop CD8- depleted, HLA-mismatched unrelated DLI for patients with myelodysplastic syndrome after failure of hypomethylating agents (HMA) or patients with secondary acute myeloid leukema. Standard therapy comprises cytarabine plus daunorubicin or idarubicin and induces CR in approximately 20-50% of patients, who then become candidates for curative allogeneic stem cell transplantation. The proposed approach minimizes the risk of GVHD and preserves the option of allogeneic stem cell transplantation from a family donor. The first clinical trial will use a standard 3+3 design to establish the maximally tolerated dose (MTD) of donor CD4+ T cells and provide an estimate of the CR rate at the MTD for the cohort of patients with MDS failing HMA. The major toxicities to be monitored are toxicities of the CD8 depletion device and toxicities of the donor lymphocytes. We anticipate that non-sustained engraftment of CD4+ T cells will be associated with an acceptable safety profile at doses of lymphocytes that will be able to be harvested from an unstimulated, unrelated donor in a single apheresis session. Reversal of T cell exhaustion and tumor specific responses will provide the rationale for comparing this novel therapy to the current standard of care.